The overdiagnosis and overtreatment of prostate cancer has become a
national public health concern. (1) Early prostate cancer detection
through widespread prostate-specific antigen (PSA) screening reduces
cancer-specific mortality and the incidence of metastatic disease in a
small proportion of men at the expense of exposing many more men to its
associated risks. (2,3) Early detection with PSA screening
over-diagnoses 23% to 42% of prostate cancer, leading to over-treatment
and its related harms. (4-6) Citing this unfavourable risk-benefit
ratio, the United States Preventative Services Task Force (USPSTF)
recommended against screening in all men. (1) While a ban on screening
would eliminate overdiagnosis entirely, it also would permit 3000 to
4000 avoidable prostate cancer deaths annually. (7) An alternative
solution to overtreatment is to restrict screening to age-appropriate
men and to limit treatment based on patient life expectancy and disease
characteristics.

Watchful waiting (WW) and active surveillance (AS) minimize
overtreatment by avoiding or delaying curative treatment in
well-selected men, respectively. Both strategies involve a period of
initial observation (IO) followed either by continued observation in
elderly or sickly men who are unlikely to benefit from active treatment
(WW) or by active monitoring with selective delayed intervention in men
at higher risk for disease progression (AS). It is now clear that
neither strategy sacrifices short-term cancer-specific survival in men
with low-risk disease. (8-11) Seemingly, the primary barrier limiting
the effectiveness of IO to combat overtreatment in this country has been
its acceptance by urologists. (12)

Historically IO has been used at very low rates in the United
States, largely relegated to use in older men. (13,14) With the
introduction of AS in 2002, IO became a feasible option for all men with
low-risk prostate cancer. (15) While recent IO usage appears to be
robust in Scandinavia, little is known about its contemporary uptake in
the United States or the factors that influence its utilization. (11,16)
We sought to examine IO utilization and its predictors in a national
sample of men using the National Cancer Database (NCDB).

Methods

The NCDB, a joint project of the American Cancer Society and the
Commission on Cancer (CoC) of the American College of Surgeons, is a
comprehensive clinical oncology dataset that captures 70% of all
incident malignancies in the United States. It has been validated
previously against the SEER (Surveillance, Epidemiology and End Results)
database. (17) The dataset contains only de-identified data, obviating
the need for institutional review board approval.

We identified 1 666 913 patients with histologically confirmed
prostate cancer based on ICD-O-3 primary site (C619) and histology
(8140) codes. The study period was limited to diagnosis years 2004 to
2011 because PSA data were not available prior to 2004 (n = 973 558).
Only patients with prostate cancer as their sole or first cancer
diagnosis were included to avoid confounding from prior cancer
treatments (n = 900 580). We limited our cohort to men with low-risk
prostate cancer by the D'Amico criteria, defined as Gleason score
<6 (no Gleason pattern 4 or 5), TNM clinical T stage T1-T2a, and PSA
<10 (n = 220 187). After excluding nodal and metastatic disease, 219
971 patients were available for analysis.

The NCDB only includes data on "first course of
treatment," defined as all methods of treatment recorded in the
treatment plan and administered to the patient before disease
progression or recurrence. IO was defined as no first course treatment.
Active treatment included prostatectomy, radiation therapy, androgen
deprivation, and other unspecified treatments (which accounted for
<3% of cases). To identify factors associated with IO utilization for
low-risk prostate cancer, we compared men who underwent IO to those who
received active treatment.

Overall, from 2004-2011, 9.7% (21 231/219 971) of men with low-risk
prostate cancer were managed with IO, while 198,740 were actively
treated. The low-risk prostate cancer population was composed of
predominantly more educated, wealthier, insured Caucasian men living in
metropolitan areas who sought care at major academic and comprehensive
cancer centers throughout the United States (Table 1). Patients were
primarily healthy and younger than age 70. Most men had clinical T1c
prostate cancer and PSA >4.

Aside from diagnosis year, clinical factors were also significant
predictors of IO usage (Table 2). In particular, age was the single
greatest predictor of IO utilization. Compared to patients <50 years,
patients >70 years had 2.5 times the odds of receiving IO (OR 2.5, CI
2.3-2.7, p < 0.01) and those >80 years had 7.2 times greater odds
(OR 7.2, CI 6.4-8.0, p < 0.01). Charlson comorbidity index (CCI) had
a small, but significant, impact on IO utilization as well. Patients
with more than one comorbidity had 10% increased odds of receiving IO
than those without comorbidities (p < 0.01). Men with PSA >4 or
clinical T2 disease were significantly less likely (10% and 30%
decreased odds, respectively) of undergoing IO than those with T1
disease or PSA <4 (p < 0.01).

Albeit to a lesser extent, demographic factors were also important
predictors of IO usage. African American and other, non-Hispanic
minority men had 20% and 30% increased odds of receiving IO compared to
Caucasian men (OR 1.2, CI 1.2-1.3; OR 1.3, CI 1.2-1.4; p < 0.01,
respectively). Less educated men and wealthier men were both
significantly less likely to receive IO (OR 0.8, CI 0.8-0.9; OR 0.8, CI
0.8-0.9; p < 0.01, respectively).

Non-clinical factors that significantly predicted IO use included:
insurance provider, hospital type, and, to a lesser degree, hospital
region. IO usage was highest in the uninsured and in patients with
social insurance. Compared to patients with private insurance, patients
with social insurance had 1.2 times the odds of receiving IO (OR 1.2, CI
1.2-1.3, p < 0.01), while uninsured patients had 2.5 times the odds
(OR 2.5, CI 2.3-2.8, p < 0.01). IO was most frequently utilized at
academic centres. Men treated at academic centres had 2.1, 1.2, and 1.9
times the odds of receiving IO compared to patients treated at
comprehensive centres, community cancer programs, and other hospitals,
respectively (p < 0.01). IO was most common in western United States,
followed by the northeast, south, and midwest regions (p < 0.01) (See
Appendix). Within a particular region, IO selection did not
significantly depend on the patient's place of residence (rural,
urban, or metropolitan, using the typology published by the United
States Department of Agriculture Economic Research Service). (18)

Discussion

From 2007 onward, IO usage increased gradually at a rate of 1.7%
per year, peaking at 14.3%. This rise may be related to greater
acceptance of AS, which was first included in clinical practice
guidelines as an alternative to active treatment in 2007. (19) In
general, however, IO use was higher in men with limited life
expectancies (age >70 and CCI [greater than or equal to] 2),
suggesting WW-predominant practice patterns. (20) This is a change from
pre-2008 trends, in which aggressive treatment was administered
regardless of patient life expectancy. (21) We found that academic
centres in the United States led the way in IO adoption. Interestingly,
men receiving IO were more likely to be poor or belong to a minority
group and were less likely to have private health insurance than their
counterparts.

While our study is one of the first to demonstrate the more recent
rise in IO utilization in the United States, our baseline IO rate (7.4%)
from 2004 to 2007 is consistent with prior research. Cooperberg and
colleagues reported an 8.5% utilization rate of observation for low-risk
prostate cancer from 2004 to 2007, using the CaPSURE database. (22) On
the contrary, Ritch and colleagues recently reported a much higher and
rising rate of observation (from 18% in 2004 to 29% in 2009) in men with
low-risk disease; however, since their data only included men age 65 and
older, these results may have been influenced by selection bias. (23)
Loeb and colleagues also noted increasing AS utilization in Sweden over
the same interval (2007-201 1). (16) However, AS rates for low- and very
low-risk disease in Sweden were much higher (41%-59%) than our IO rates,
possibly reflecting both cultural and financial disparities in practice
patterns between the United States and Scandinavia. (16)

It is estimated that 38% to 60% of patients diagnosed with early
prostate cancer are considered low risk by D'Amico criteria and
thus are candidates for management with IO. (11,24) Based on these
estimates, our findings suggest that IO is still being underutilized in
the United States despite its recent gains. The reasons behind
underutilization are likely multifactorial.

The lack of clear recommendations favouring AS may have contributed
to IO underutilization. For most of the diagnosis period (2004-2007), AS
was not an accepted strategy for low-risk prostate cancer. (18) Also,
preliminary results from the largest prospective AS cohort (Prostate
Cancer Research International: Active Surveillance, PRIAS), were not
available until 2009.25 Moreover, the limited benefit of active
treatment for low-risk, screen-detected prostate cancer was not yet
known. (8) Consequently, community urologists may have considered AS
experimental, explaining why academic centres were primarily responsible
for the rise in IO use.

Racial/ethnic and socioeconomic disparities in treatment selection
for prostate cancer are well-recognized. It has been shown that
African-American men are more likely to be managed expectantly than
white men. (26) Similarly, poor men and men with public health insurance
are more likely to be treated conservatively. (27,28) In keeping with
these disparities, we found that minority men, especially
African-Americans, men from lower socioeconomic groups, and uninsured or
socially insured men preferentially received IO. While increased IO
utilization as a whole should be considered an achievement, its
preferential use in certain racial and socioeconomic groups is not
evidence-based and may be detrimental. In particular, African-American
men, who have a higher disease progression rate on AS, may not be the
best candidates for this approach. (29) Furthermore, poor men may
experience inferior outcomes when managed conservatively. (28)

It is unclear why poor and uninsured or underinsured men were more
inclined to receive IO. This disparity does not appear to be caused by
local differences in resource availability, since area of residence did
not affect IO selection. Given that IO is associated with lower upfront
costs than active treatments, it is possible that financial
considerations influenced treatment decisions. (30) This also may
explain why non-academic/non-research hospitals, which rely on
fee-for-service reimbursement, preferentially utilized higher-cost
treatments. In contrast, at government-sponsored Veterans Affairs
hospitals, which are less influenced by reimbursement concerns, IO
utilization is higher. (31)

There are significant barriers to widespread AS adoption in the
United States. While patient anxieties may limit utilization, physician
influence is the single most important factor influencing the decision
to undergo AS. (12,32) Interestingly, we found that education level was
associated with treatment selection, with educated men more likely to
choose IO. Men with poor prostate cancer knowledge have more decisional
conflict and decision-making impairment than educated men, potentially
explaining their reluctance to pursue AS. (33) Urologists must promote
AS, educating and reassuring low-risk patients on the benefits of IO
relative to active treatment.

A clear strength of our study is the NCDB's comprehensiveness,
capturing over 70% of incident cancers in the United States regardless
of age. Since hospitals included in the NCDB exhibit higher levels of
cancer specialization than other hospitals, our findings may demonstrate
the best-case scenario in terms of contemporary IO utilization.

The main limitation of this study is its retrospective nature.
Since the NCDB does not code IO as a unique treatment, we used lack of
treatment to define IO. This definition is somewhat flawed because
treatment delay may be erroneously construed as IO, leading to
misclassification and overestimation of the IO rate. Fortunately, the
NCBD makes every effort to assign treatments appropriately to minimize
this error. Similarly, the NCDB does not differentiate AS from WW, nor
does it include data on number of positive cores, re-biopsies or
second-course treatments, limiting our ability to selectively identify
AS patients.

Conclusion

IO has been utilized increasingly for low-risk prostate cancer in
the United States, especially in patients least likely to benefit from
active treatment. Despite this progress, IO is still underutilized,
possibly due to the influence of non-clinical factors. The future of AS
and, for that matter, of prostate cancer diagnosis depends on the
continued adoption of IO by urologists.

Acknowledgements: An abstract of the work was presented at the
American Society of Clinical Oncology Genitourinary Cancers Symposium in
San Francisco, CA on January 30, 201 4 and at the American Urological
Association annual meeting in Orlando, FL on May 20, 201 4. The American
College of Surgeons and the Commission on Cancer have not verified and
are not responsible for the analytic or statistical methodology
employed, or the conclusions drawn from these data by the investigator.